Endogenous lysophosphatidic acid (LPA 1 ) receptor agonists demonstrate ligand bias between calcium and ERK signalling pathways in human lung fibroblasts.

Autor: Sattikar A; Novartis Institutes for Biomedical Research, Horsham, UK., Dowling MR; Novartis Institutes for Biomedical Research, Cambridge, MA, USA., Rosethorne EM; Novartis Institutes for Biomedical Research, Horsham, UK.; School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2017 Feb; Vol. 174 (3), pp. 227-237. Date of Electronic Publication: 2017 Jan 06.
DOI: 10.1111/bph.13671
Abstrakt: Background and Purpose: Human lung fibroblasts (HLF) express high levels of the LPA 1 receptor, a GPCR that responds to the endogenous lipid mediator, lysophosphatidic acid (LPA). Several molecular species or analogues of LPA exist and have been detected in biological fluids such as serum and plasma. The most widely expressed of the LPA receptor family is the LPA 1 receptor, which predominantly couples to G q/11 , G i/o and G 12/13 proteins. This promiscuity of coupling raises the possibility that some of the LPA analogues may bias the LPA 1 receptor towards one signalling pathway over another.
Experimental Approach: Here, we have explored the signalling profiles of a range of LPA analogues in HLF that endogenously express the LPA 1 receptor. HLF were treated with LPA analogues and receptor activation monitored via calcium mobilization and ERK phosphorylation.
Key Results: These analyses demonstrated that the 16:0, 17:0, 18:2 and C18:1 LPA analogues appear to exhibit ligand bias between ERK phosphorylation and calcium mobilization when compared with 18:1 LPA, one of the most abundant forms of LPA that has been found in human plasma.
Conclusion and Implications: The importance of LPA as a key signalling molecule is shown by its widespread occurrence in biological fluids and its association with disease conditions such as fibrosis and cancer. These findings have important, as yet unexplored, implications for the (patho-) physiological signalling of the LPA 1 receptor, as it may be influenced not only by the concentration of endogenous ligand but the isoform as well.
(© 2016 The British Pharmacological Society.)
Databáze: MEDLINE
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